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Tetrahydrobiopterin (BH4, THB, trade name Kuvan) or sapropterin (INN) is a naturally occurring essential cofactor of the three aromatic amino acid hydroxylase enzymes, used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotonin (5-hydroxytryptamine, 5-HT), melatonin, dopamine, norepinephrine (noradrenaline),epinephrine (adrenaline), and is a cofactor for the production of nitric oxide (NO) by the nitric oxide synthases.
was discovered to play a role as an enzymatic cofactor. The first
enzyme found to use tetrahydrobiopterin is phenylalanine
is biosynthesized from guanosine triphosphate (GTP) by three chemical
reactions mediated by the enzymes GTP cyclohydrolase
I (GTPCH), 6-pyruvoyltetrahydropterin synthase (PTPS), and sepiapterin
Tetrahydrobiopterin has the following responsibilities as a cofactor:
- Tryptophan hydroxylase (TPH) for the conversion of L-tryptophan (TRP) to 5-hydroxytryptophan (5-HTP)
- Phenylalanine hydroxylase (PAH) for conversion of L-phenylalanine (PHE) to L-tyrosine (TYR)
- Tyrosine hydroxylase (TH) for the conversion of L-tyrosine to L-DOPA (DOPA)
- Nitric oxide synthase (NOS) for conversion of a guanidino nitrogen of L-arginine (L-Arg) to nitric oxide (NO)
- Alkylglycerol monooxygenase (AGMO) for the conversion of 1-alkyl-sn-glycerol to 1-hydroxyalkyl-sn-glycerol
has multiple roles in human biochemistry. One is to convert amino acids
such as phenylalanine, tyrosine, and tryptophan to precursors of
dopamine and serotonin, the body's primary neurotransmitters). Due to
its role in the conversion of L-tyrosine in to L-dopa, which is the
precursor for dopamine, a deficiency in tetrahydrobiopterin can cause
severe neurological issues unrelated to a toxic buildup of
L-phenylalanine; dopamine is a vital neurotransmitter, and is the
precursor of norepinephrine and epinephrine. Thus, a deficiency of BH4
can lead to systemic deficiencies of dopamine, norepinephrine, and
epinephrine. In fact, one of the primary conditions that can result from
GTPCH-related BH4 deficiency is dopamine-responsive dystonia;
currently, this condition is typically treated with carbidopa/levodopa,
which directly restores dopamine levels within the brain.
also serves as a catalyst for the production of nitric oxide. Among
other things, nitric oxide is involved in vasodilation, which improves
systematic blood flow. The role of BH4 in this enzymatic process is so
critical that some research points to a deficiency of BH4 – and thus, of
nitric oxide – as being a core cause of the neurovascular dysfunction
that is the hallmark of circulation-related diseases such as diabetes.
FROM DR. AMY YASKO
The BH4 Three-Legged Stool
added ammonia that is generated due to the enhanced breakdown of
methylation cycle intermediates will also burden the adjoining urea
cycle, thereby depleting a key intermediate called BH4, which plays a
critical role in regulating neurotransmitters and therefore mood. BH4 is
needed for serotonin, dopamine, conversion of phenylalanine to tyrosine
and language-related function. The A1298C mutation in the MTHFR gene
may also impact levels of BH4.
drawing of a three-legged stool can help you visualize how the body
maintains adequate levels of BH4. One leg is for CBS upregulations. The
second leg is for MTHFR A1298C, another key SNP on the methylation
pathway, which you will learn more about later in this chapter. The
third leg is chronic bacteria/ aluminum. Stable BH4 levels require all
upregulations weaken one leg of the stool by using up BH4 faster than
it can be supplied. The NOS mutation can also exacerbate the CBS ammonia
problem. In the adjacent urea cycle, inefficient NOS activity can lead
to elevated ammonia levels, further draining BH4 limited stores.
Reciprocally, CBS upregulations strain the urea cycle, where BH4 is
needed to form nitric oxide. The formation of nitric oxide requires two
BH4 molecules. With insufficient BH4, the body will instead produce
peroxy nitrite (with one BH4 molecule), or super oxide (if no BH4 is
available.) These two products can cause oxidative damage. The
combination of CBS + and these other SNPs will further weaken this leg
of the BH4 stool.
A1298C mutations (if present) impair the second leg by disrupting the
recycling and regeneration of BH4. Chronic bacterial infection (which
can lead to aluminum retention) weakens the third leg of the stool,
because aluminum inhibits a key enzyme that helps to synthesize BH4. On
this program, you will ultimately address all three legs of the BH4
stool by supporting the body to address chronic bacteria/aluminum,
supporting the MTHFR A1298C mutation, and addressing CBS/ammonia issues.
Other Interfaces that Impact BH4
mutations can also improve (or worsen) our BH4 stool’s sturdiness.
While BH4 helps in the formation of neurotransmitters, other factors
contribute to neurotransmitter breakdown. Bacterial infections trigger a
more rapid breakdown of tryptophan (needed for serotonin). Low levels
of BH4 have been associated with hypertension and arteriosclerosis, as
well as with more severe parasitic infections. Parasitic infections also
deplete B12 levels, impacting methylation cycle function.
of BH4 may result in mast cell degranulation and lead to higher
histamine levels, which can produce symptoms such as red ears and other
hypersensitivity reactions. Serotonin synthesis as well as ammonia
detoxification also require BH4. Elevated ammonia levels can cause
flapping and other over-stimulatory behaviors.
that lead to more ammonia, such as high protein diets, generate more
ammonia that needs to be detoxified. Each molecule of ammonia requires
two molecules of BH4 for ideal detoxification. Excess ammonia in the gut
may alter the pH and aggravate imbalances in microbial flora. It’s
obvious how these factors interact to impact ammonia detoxification as
well as optimal BH4 levels for neurotransmitter synthesis. Keeping the
ammonia levels under control is of paramount importance for overall
health and wellness, especially for those with an MTHFR A1298C mutation,
as any excess ammonia generated can drain stores of BH4. This can
affect serotonin levels and to a certain extent cause fluctuations in
dopamine (which translates into mood swings). Helping to restore
adequate levels of BH4 should also aid in serotonin synthesis,
maintaining dopamine levels as well as ammonia detoxification in a more
Test Results Indicating Decreased BH4
- High hippuric
- Increased 8 hydroxy 2 deoxy guanosine (lack of SAMe or high ammonia can also cause increased 8 hydroxy 2 deoxy guanosine)
- Elevated phenylalanine, phenyl lactate, phenyl acetate, and/or phenylethylamine
- Increased ammonia
- Until we support the methylation cycle, we are not going to see the full impact of the CBS upregulations.
collaborative research is ongoing with a group of doctors in Japan
looking at the use of prescription BH4 to help to compensate for MTHFR
A1298C and CBS C699T+ mutations. The initial results are encouraging.
Low daily doses of BH4 (1.25 mg) initially appear to stimulate
detoxification over the first several weeks of use. After this initial
detoxification effect, the BH4 appears to have a very positive impact on
language for individuals with CBS C699T+ mutations. It seems it is
possible to restore BH4 stores through supplementation.
Vitamin C (as ascorbic acid) 10 mg, Tetrahydrobiopterin (a stable form of the physiologic agent, biopterin) 2.5 mg. Other ingredients: Sucrose, Gelatin, L-Leucine.